The disclosure relates generally to transdermal drug delivery, and more particularly to transdermal compositions and methods of administering an active agent comprising pramipexole and/or its related compounds in a single dose for extended periods, typically two days or greater. The invention additionally relates to a non-occlusive transdermal therapeutic system semi-solid composition containing pramipexole, which is chemically stable.
The transdermal route of parenteral drug delivery provides many advantages over other administrative routes. Transdermal drug delivery devices, including multilaminates and monoliths, for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,588,580; 4,645,502; 4,698,062; 4,704,282; 4,725,272; 4,781,924; 4,788,062; 4,816,258; 4,849,226; 4,904,475; 4,908,027; 4,917,895; 4,938,759; 4,943,435; 5,004,610; 5,071,656; 5,141,750; 5,342,623; 5,411,740; and 5,635,203.
One problem associated with the devices of the prior art is degradation of the pharmaceutical active ingredient, as well as certain contents of the device, such as permeation enhancers, matrix materials, or other components. Degradation can result from both internal and external conditions. Internal conditions include the presence of inactive ingredients such as acid, base and oxidants, which may react with and degrade the active pharmaceutical ingredients (APIs). Impurities from these inactive ingredients not only undesirably break down these materials, but can also cause discoloration and formation of odors even within a system which separates the active ingredients from external conditions, such as heat, light, moisture and oxygen, e.g., by use of an envelope or pouch. Devices susceptible to degradation cannot be stored for a commercially reasonable amount of time, thus causing practical problems in their distribution.
Pramipexole is used for the treatment of neurological disclosures, e.g., Parkinson's disease. Pramipexole's structural formula is set out below.

As a dopamine agonist, pramipexole [2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole] binds with high selectivity and specificity to the D2 and D3 receptors. Owing to its stimulating effect on the dopamine receptors in the corpus striatum, pramipexole produces a reduction in Parkinson's tremors. When administered orally, the daily dose is approximately from 1.5 to 4.5 mg with a bioavailability of 90%. However, the administration of even small amounts of pramipexole is associated with considerable side-effects in the patient.
A transdermal therapeutic system avoids side-effects that occur in the case of oral administration of pramipexole. Transdermal administration furthermore has the advantage that the active ingredient, after permeation through the skin, has a direct systemic action, as a result of which a constant blood plasma level can be guaranteed. Hepatic metabolism of the active ingredient is also circumvented. Gastrointestinal side-effects are avoided.
EP-B1-0 428 038 discloses a transdermal system having a content of pramipexole and a) an active-ingredient-impermeable backing layer which is at the same time constructed as a covering plaster, b) an active-ingredient-containing reservoir (preferred carrier for the active ingredient is an emulsion-polymerised polyacrylate of the type Eudragit NE 30 DR produced by Rohm GmbH, Darmstadt) and c) a peel-off protective film (release liner).
Owing to surfactants or plasticizers and surface-active substances used in an emulsion-polymerized polyacrylate, a TTS produced according to EP-B1-0 428 038 does not exhibit sufficient stability of the active ingredient. In that matrix, pramipexole decomposes very rapidly, with discoloration occurring. In addition, the active ingredient crystallizes out, resulting in insufficient storage stability.
U.S. Published Application 2008/076913 discloses a pharmaceutical composition for transdermal or transmucosal delivery of an active agent such as pramipexole to treat a movement disorder such as Parkinson's disease. The composition includes an alkanolamine as a permeation enhancer with a carrier of water and at least one short-chain alcohol and with the composition having a neutral pH. The composition provides controlled and sustained release of the active agent suitable for daily administration.
U.S. Published Application 2011/0151003 discloses a transdermal drug delivery device package which comprises a backing layer substantially impervious to the drug being delivered, a drug reservoir adhesive layer, a skin contact adhesive layer wherein each adhesive layer provides a different rate of drug delivery therefrom, and a release liner whose removal exposes the skin contact adhesive layer. The resulting dosage units are stored in appropriate packaging until used.
U.S. Pat. No. 7,344,733 describes preparation of a matrix-controlled transdermal therapeutic system for the use of pramipexole and ropirinole, which contains acrylic, silicone and polyisobutene (PIB) pressure-sensitive adhesives (PSAs). The '733 patent, teaches actives ranging from 2 to 15% by weight of the weight of the matrix, as well as exemplified embodiments which use a concentration of not more than 4% w/w active ingredient which is stable in terms of discoloration, with no crystal growth and a flux profile of only 24 hours.
U.S. patent application Ser. No. 13/624,390, filed Sep. 21, 2012 discloses transdermal delivery devices for drugs which are subject to degradation during storage by hydrolysis and/or oxidation, e.g., rivastigmine.
U.S. patent application Ser. No. 13/570,593, filed Aug. 9, 2012 discloses a method for treating severe headaches, e.g., cluster headaches and migraines, using transdermal administration of pramipexole.
It would be desirable to provide a transdermal drug delivery device package which provides controlled and sustained release of an active agent, e.g., dopamine agonist, such as pergolide, lisuride and/or pramipexole, for an extended period of time of more than one day, e.g., two days, three days, or a week or more, to treat hypokinetic disorders such as Parkinson's disease. It would further be desirable to provide a transdermal drug delivery device package which allows the use of highly concentrated active ingredient(s), e.g., pramipexole at greater than about 5 wt. % of the matrix in which it found, which exhibits a therapeutically effective flux profile over an extended period, e.g., at least two days, a one week period or even longer. It would also be desirable to provide a transdermal drug delivery device package which, while using highly concentrated active ingredient(s), still exhibits formulation stability of its active ingredient(s). Such a device would avoid or minimize substantial discoloration or substantial crystal growth over extended storage periods, e.g., at least one month or longer.